Bactericide applicable to acid-fast bacteria



Patented-Aug. 23,; 1932- UNITED STATES PATENT m m:

ROGER ADAMS, OF URBANA, ILLINOIS, ASSIGNOR TO ABBOTT LABORATORIES, OF NORTH CHICAGO, ILLINOIS, A CORPORATION OF ILLINOIS BACTERICIDE APPLICABLE TO ACID-FAST BACTERIA No Drawing.

This invention relates to the preparation of aliphatic acids and derivatives of these acids. These compounds have the general formula HOOOZ, R/ where R and R represent aliphatic-hydrocarbon radicals such as alkyl or alkylene, and m where Z represents a hydrogen atom, an alkali or alkaline earth metal or a hydrocarbon radical. I v

Chaulmoogra oil, chaulmoogric acid, and homologues of chaulmoogric acid and their derivatives have long been known to be effective in combating certain diseases such as leprosy, produced by acid-fast bacteria.

Such chaulmoogra derivatives contain an unsaturated five membered carbon ring to which the activity against the leper bacilli was formerly attributed. Recent discoveries have shown that a variety of other acids which contain other types of carbon rin are also effective against such acid-fast bac- 95 teria.

My further discoveries seem to demonstrate that a ring structure is not necessary but that the number of carbon atoms, the molecular weight of the compounds, and the position of the carboxyl group in the chain, are the important factors in determining the bactericidal and bacteriostatic efiiciency of the products. (The term bacteriostatic means preventing growth of bacteria, as 8 distinguished from bactericidal which means bacteria destroying.) Compounds containing more than nine and less than twenty-two carbon atoms appear to be most efiicient, particularly those containing 15 to 18 carbon atoms. The presence or absence of a ring structure seems to be of minor importance.

The discovery of the bactericidal efiiciency of these acids described in this application is of particular importance since certain analogous compounds, which are very well known, such as stearic acid, show no appreciable germicidal efliciency whatsoever. In stearic acid, the carboxyl group is at the end of the chain of seventeen carbon atoms. I are prepared are given as illustrations of the 10f Application filed December 28, 1928. Serial No. 829,077.

have found that if the carboxyl group is removed from this position, and placed farther down towards the center of the chain, the efficiency is markedly increased. The highest efliciency seems to reside in such compounds in which the carboxyl group is attached to the middle carbon atom or to a .carbon atom that is near the middle.

These acids have the additional advantage that they may be prepared and made available for therapeutic use much more readily than is the case with the ring containing compounds previously studied.

These acids may be prepared by introducing the hydrocarbon radicals successively into an ester with an active methylene group, which then on treatment with alkalies, can yield a substituted acetic acid. Examples of such esters are malonic ester and acetoacetgic ester. Illustrating with malonic ester, the reactions involved are as follows, where R and R are aliphatic alkyl radicals, such as alkyl or alkylene ooocim coocun 00002115 RCH/ cooo m 00001115 ROB +NaBr+CzHH.

cooozm OOOCzHs ROB. +2NaOH- ROR ooooun ooom OOONa coon no R +2no1 ROR' +2Na01 COONa coon ROE coon heat R oooH The following examples of such acids and some of their intermediates from which they straight chains. Wherever two formulae are K invention. Unless otherwise indicated in the formula, the hydrocarbon radicals are given, the first mentioned formula refers to the intermediate diethyl dialkyl malonates.

Melting Boiling point point C4HBCH(COOH)C4HQ 153:]lfimm C4HoCH(COOCzH5) C4H 114-115 /15mm 1soC5HuCH(COOH)1so 158 15mm 146r149/2. 5mm 160162/2mm 187188/9mn1 196198/ 10mm 185186/9mm 148150/3mm 149-151/1mm 167l69/4mm 164-166/2mm 179-183/3mm 186138/1mm 175180/3mm 186-190/3mm 200204/3mm 205209/3mm As an example, ethyl di-n-heptyl acetate is representative of the group of compounds covered. by the application, which is being used clinically. The substance is administered in an equal mixture of olive oil, preferably with two per cent anesthesin, added to reduce the pain of injection, although the anesthesin is not required. That is to say, one part of the compound is mixed with an equal part of olive oil, and to this is added a quantity of anesthesin equal to two per cent of the total weight. About five to six cc. of the mixture is injected intramuscularly once a week. However, the administration can be varied substantially, both as to amount and the frequency. The quantities and method of administration of the other materials mentioned above will be similar.

The scope of the invention should be determined by reference to the appended claims, said claims being construed as broadly as possible consistent with the state of the art.

I claim as my invention:

1. As a new bactericidal or bacteriostatic agent, an aliphatic substance containing from 10 to 21 carbon atoms and having the general formula CHCOOZ, R!

where R and R represent aliphatic hydrocarbon radicals such as alkyl or alkylene, and Where Z represents a hydrogen atom, an alkali or alkaline earth metal or a hydrocarbon radical.

2. As a new bactericidal or bacteriostatic agent, an aliphatic substance containing from 15 to 18 carbon atoms and having the general formula onoooz, RI

where R and R represent aliphatic hydrocarbon radicals such as alkyl or alkylen-e, and where Z represents a hydrogen atom, an alkyli or alkaline earth metal or a hydrocarbon radical.

3. As a new bactericidal or bacteriostatic agent, an aliphatic substance containing from 10 to 21 carbon atoms and having the general formula CHCOOZ, R!

where R and R represent aliphatic hydrocarbon radicals such as alkyl or alkylene, and where Z represents a hydrogen atom, an alkali or alkyline earth metal or a hydrocarbon radical, and Where the carboxyl group is attached near the middle of the chain.

4. As a new bactericidal or bacteriostatic agent especially applicable to acid-fast bacteria, a substance which is a member of the group consisting of aliphatic acids, alkali and alkaline earth metal salts thereof and hydrocarbon esters thereof, in which the carboxyl group is located at a point removed from the end of the chain, said substance containing from 10 to 21 carbon atoms.

5. A composition as defined in claim 4, and containing from 15 to 18 carbon atoms.

6. As a new bactericidal or bacteriostatic agent especially applicable to acid-fast bacteria, a substance which is a member of the group consisting of aliphatic acids, alkali and alkaline earth metal salts thereof, and

hydrocarbon esters thereof, in which the carboxyl group is attached to a carbon atom at approximately the center of the chain, said substance containing from 10 to 21 carbon atoms.

7. A composition as defined in claim 6, and

containing from 15 to 1 8 carbon atoms. ROGER ADAMS. 

